JPH06321771A - Base for percutaneous administration - Google Patents

Abstract

PURPOSE:To obtain a base for percutaneous administration having good percutaneous permeability, excellent in absorption promoting effect by containing an aliphatic acid ester, an alcohol and water. CONSTITUTION:0.1-50% Fatty acid ester (e.g. isopropyl myristate), 10-90% alcohol (e.g. ethanol) and 1-80% water based on the total amount of the three components are compounded to obtain the objective base. This base is further compounded with a medical compound to obtain a medicine for percutaneous administration. The base for percutaneous administration can penetrate even a medicinal compound, which has been relatively difficult in using for percutaneous administration, through horny layer of skin with high permeability, thus various medicinal compounds are effectively administered on skin. Further, a lag time until the medicinal compound is percutaneously absorbed is shortened, skin irritation is very slight and the base is excellent in safety.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel base for transdermal administration,
It also relates to a novel transdermal preparation containing a pharmaceutical compound in the base.

[0002]

2. Description of the Related Art When a drug is orally administered, depending on the drug, the bioavailability is lowered due to the first-pass effect in the liver, it is decomposed in the digestive tract, and the absorption from the digestive tract mucosa is reduced. There is. Oral administration may be difficult for the elderly and bedridden patients. Therefore, recently, the advantages of transdermally administering a drug have been attracting attention, such as convenience of administration, sustainability of efficacy, and reduction of side effects.

However, when a drug is transdermally administered, the stratum corneum of the skin epidermis has a barrier function against drug absorption, so that there is a problem that the drug permeation rate in the stratum corneum is low, and the drug is administered. When the drug is highly lipophilic, the dermis also impairs permeation. In order to solve this problem, Azone (chemical name: 1-dodecylazacycloheptan-2-one), menthol, alkylmethyl sulfoxide, pyrrolidone and the like are used as transdermal absorption enhancers. In addition, among the bases for transdermal administration, for example, alcohols, fatty acids, fatty acid esters and the like which are themselves base components and have a transdermal absorption promoting effect are also known. Furthermore, for example, (a) higher alcohols such as lauryl alcohol and oleyl alcohol, (b) higher fatty acids such as oleic acid and lauric acid, and (c) ethanol and isopropyl alcohol,
A combination of a specific base and a specific drug, such as a transdermal preparation (JP-A-2-152921) in which a β-blocker such as propranolol hydrochloride is mixed with a base composed of one kind or a mixture of two or more kinds of water. Therefore, a transdermal preparation having improved absorption promoting property is also known.

[0004]

However, in reality, the above-mentioned percutaneous absorption enhancer is highly irritating and has a problem in safety, so that there are restrictions in actual use, Even when the base is combined as described above, it does not exert an effect on a large number of pharmaceutical compounds, but often exerts an effect only on a specific pharmaceutical compound. On the other hand, no substance having an absorption promoting effect was known.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a combination of a fatty acid ester, an alcohol and water has been compared to the transdermal administration until now. It was found that even a difficult-to-treat pharmaceutical compound can pass through the epidermis and dermis with high transmittance, the lag time in drug absorption can be shortened, and this effect can be exerted only by the base in which the three components are combined. Together, it has been found that the base can be applied to numerous pharmaceutical compounds. Although the mechanism of the excellent absorption-promoting effect of such a base cannot be said to be clear, for example, fatty acid esters mainly partition into the stratum corneum of the skin due to its fat solubility and interact with stratum corneum lipids, and alcohols Both hydrophilic and lipophilic substances dissolve and play a role of a carrier for drug permeation through the skin. In particular, lower monohydric alcohols such as ethanol also have the action of increasing the fluidity of the stratum corneum and extracting the stratum corneum lipids. Furthermore, water increases the hydration of the skin, increases the drug solubility in the base for hydrophilic drugs, and promotes the escape tendency from the base for lipophilic drugs and fatty acid esters. It is considered that the combination of the components may have synergistically enhanced absorption promoting effect.

That is, the present invention is a transdermal administration base comprising a fatty acid ester, alcohols and water, or a transdermal administration preparation in which a pharmaceutical compound is mixed.

In the present invention, examples of the fatty acid ester include (A) fatty acid having 1 to 32 carbon atoms and 1 to 1 carbon atom.
Examples thereof include an ester of 30 with an aliphatic monohydric alcohol and (B) an ester of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms with a mono- or polyvalent glycerin.

Examples of (A) include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecyl acid,
Lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid, heptadecyl acid, stearic acid,
Oleic acid, nonadecanoic acid, arachidic acid, tosuccinic acid,
Linoleic acid, Linolenic acid, Lindelic acid, Arachidonic acid,
Sebacic acid, behenic acid, lignoceric acid, cerotic acid,
Fatty acids such as heptacosanoic acid, montanic acid, melissic acid, laxeric acid, elaidic acid and brassic acid, and methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol, ter
t-butyl alcohol, n-amyl alcohol, isoamyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, capryl alcohol, nonyl alcohol, decyl alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl. Esters with aliphatic monohydric alcohols such as alcohol, isocetyl alcohol, hexadecyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, octyldodecyl alcohol, nonadecyl alcohol, eicosyl alcohol, ceryl alcohol, and melisyl alcohol. To be

Of these, preferred fatty acid esters include caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecyl acid, lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid,
Heptadecyl acid, stearic acid, oleic acid, nonadecanoic acid, arachidic acid, tosuccinic acid, linoleic acid, linolenic acid, linderic acid, arachidonic acid, sebacic acid, behenic acid, lignoceric acid, cerotic acid, heptacosanoic acid, montanic acid, mericinic acid , Laxeric acid, elaidic acid, brassic acid, etc., having 6 to 32 carbon atoms, especially 6 to 1 carbon atoms
8 fatty acids, methyl alcohol, ethyl alcohol,
Propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, cetyl alcohol,
Examples thereof include esters with an aliphatic monohydric alcohol having 1 to 20 carbon atoms, particularly 3 to 20 carbon atoms, such as isocetyl alcohol, stearyl alcohol, and octyldodecyl alcohol.

Specifically, for example, methyl caprate,
Ethyl caprate, isopropyl caprate, butyl caprate, methyl caproate, ethyl caproate, isopropyl caproate, butyl caproate, methyl palmitate, ethyl palmitate, butyl palmitate, isopropyl palmitate, isostearyl palmitate, myristin Fatty acid esters such as methyl acidate, ethyl myristate, butyl myristate, isopropyl myristate, isocetyl myristate, octyldodecyl myristate, butyl stearate, isocetyl isostearate, ethyl linoleate, isopropyl linoleate and butyl linoleate. .

Of these, isopropyl caprate, isopropyl caproate, isopropyl palmitate, isopropyl myristate, butyl palmitate, butyl myristate, octyldodecyl myristate, butyl stearate, isocetyl isostearate, isopropyl linoleate, linoleic acid. Butyl and the like are preferable, and isopropyl caprate, isopropyl caproate, isopropyl myristate, isocetyl isostearate, butyl stearate, isopropyl palmitate, and octyldodecyl myristate are particularly preferable.

Further, as (B), capric acid, undecyl acid, lauric acid, tridecyl acid, myristic acid,
Pentadecyl acid, palmitic acid, heptadecyl acid, stearic acid, oleic acid, nonadecanoic acid, arachidic acid, linoleic acid, linolenic acid, behenic acid, etc. 10 to 2 carbon atoms
Esters of 2, especially saturated or unsaturated fatty acids having 12 to 18 carbon atoms with monoglycerin or polyglycerin, especially mono to hexaglycerin are mentioned.

Specifically, for example, glyceryl monolinoleate, glyceryl monoisostearate, glyceryl monolaurylate, glyceryl monomyristate, glyceryl monostearate, glyceryl monooleate, glyceryl dilaurylate, glyceryl dimyristate, glyceryl. Distearate, glyceryl trilaurate, glyceryl trimyristate, glyceryl tristearate, or diglyceryl monostearate, diglyceryl monooleate, diglyceryl monoisostearate, diglyceryl dioleate, diglyceryl monolaurate, hexa Glyceryl monolaurylate, hexaglyceryl monomyristate, hexaglyceryl monostearate, hexaglyceryl monooleate, decaglyceryl monomyristate Door, decaglyceryl monostearate, decaglyceryl monooleate, such as decaglyceryl Reno rate, and the like. Of these, glyceryl monooleate, glyceryl diolate, glyceryl isostearate, hexaglyceryl monolaurate,
Hexaglyceryl monomyristate and the like are preferable, and hexaglyceryl monolaurate and glyceryl monooleate are particularly preferable.

Further, alcohols which are another component constituting the base of the present invention include, for example, 2 to 2 carbon atoms.
There are 12 monohydric or polyhydric alcohols. Examples of monohydric alcohols include aliphatic saturated or unsaturated monohydric alcohols, and specific examples include ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec.
-Butyl alcohol, tert-butyl alcohol, n
-Amyl alcohol, isoamyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, capryl alcohol, nonyl alcohol, decyl alcohol, undecyl alcohol, lauryl alcohol and the like.

Of these, preferred are, for example, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, hexyl alcohol, Examples thereof include aliphatic alcohols having 2 to 10 carbon atoms such as heptyl alcohol and octyl alcohol.

Further preferred are ethyl alcohol, propyl alcohol, isopropyl alcohol,
C2-C2, such as butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-amyl alcohol, and isoamyl alcohol
5, aliphatic alcohols are mentioned, and the most preferable ones are ethyl alcohol, isopropyl alcohol,
Butyl alcohol is an example.

Examples of the polyhydric alcohol include aliphatic saturated or unsaturated polyhydric alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, glycerin α-monochlorohydrin and 1,2-
Butanediol, 1,3-butanediol, 2,3-butanediol, 1,4-butanediol, isobutylene glycol, pentamethylene glycol, trimethylethylene glycol, hexamethylene glycol, 2,5
Examples include aliphatic dihydric alcohols such as -hexanediol, 2-methyl-2,4-pentadiol, butanediol, 2-butyne-1,4-diol, and aliphatic polyhydric alcohols such as glycerol.

Of these, ethylene glycol, propylene glycol, 1,2-butanediol, 1,3-butanediol, glycerin and the like are preferable, and propylene glycol, 1,3-butanediol and glycerin are particularly preferable.

Water, which is another component of the base, is
Usually, it can be suitably used as long as it has properties that are used in the field of pharmaceutical preparations. Furthermore, depending on the properties of the pharmaceutical compound, salts, sugars, polymeric substances, etc. and pH can be added to this water. It is also possible to add an acid or alkaline substance for controlling the above.

The mixing ratio of each component in the base of the present invention may be appropriately determined according to the target pharmaceutical compound, and those skilled in the field of formulation are particularly required to find the optimum range. There is no difficulty. For example, when the three components are mixed, the optimum range can be determined with the index that the components do not cause separation and are compatible with each other or have a composition close thereto. Alternatively, among the components constituting the present invention, the compatibility may change depending on the number of carbon atoms of the fatty acid ester or alcohols to be combined, or even when an additive such as acid or alkali is added to water. Even if compatibility is not used as an index, it is easy to prepare a base in which the proportions of the three components are appropriately changed, add the target pharmaceutical compound to this, and study the skin permeability by a conventional method. It is possible to obtain the desired base composition.

As an example of a preferable blending ratio,
A ratio of about 0.1-50% of fatty acid ester, about 10-90% of alcohol, and about 1-80% of water can be mentioned with respect to the total capacity of fatty acid ester, alcohols and water. As an example of a more preferable blending ratio, a fatty acid ester is about 1-30%, alcohols is about 25-80%, and water is about 1-50%. Further, the blending ratio will be described based on the number of carbon atoms of the alcohol. When the alcohol is a monohydric or polyhydric alcohol having 4 or less carbon atoms, the alcohol content is about 10-9.
The content of the fatty acid ester may be 0%, and the fatty acid ester may be appropriately mixed within the range. In this case, when an ester of a fatty acid having about 10 to 32 carbon atoms and an aliphatic monohydric alcohol is used as the fatty acid ester, the fatty acid ester is used. Is about 0.1-50% if it is liquid at room temperature, about 0.1-30% if it is solid at room temperature, and 1-80% with water.

In the above, when an ester of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms and monoglycerin or polyvalent glycerin is used as the fatty acid ester, the hydrophilic / lipophilic balance (HL) of the fatty acid ester is used.
B: hydrophile-lipophile ba
Lance) is 9.0 or more, it is suitable that fatty acid ester is about 5-50% and water is about 10-80%, and if the hydrophilic / lipophilic balance is less than 9.0. It is suitable that the fatty acid ester is 0.1-30% and the water is 1-40%.

Further, when the alcohol is a monohydric or polyhydric alcohol having 5 or more carbon atoms, the amount of the alcohol may be about 10-90%, and water and fatty acid ester may be appropriately blended within the range. In this case, when an ester of a fatty acid having 10 to 32 carbon atoms and an aliphatic monohydric alcohol is used as the fatty acid ester, if the fatty acid ester is liquid at room temperature, about 0.1-30%, room temperature If it is a solid, make it about 0.1-20% and add about 1-8 water.
It is suitable to be 0%, and when an ester of a saturated or unsaturated fatty acid having about 10 to 22 carbon atoms and monoglycerin or polyglycerin is used as the fatty acid ester, the hydrophilic lipophilic balance of the fatty acid ester is used. Is 9.
If it is 0 or more, fatty acid ester is about 5-50%, water is about 10-80%, and if the hydrophilic / lipophilic balance is less than 9.0, fatty acid ester is about 0.1-30%,
A water content of about 1-40% is suitable.

All of the above combinations are suitable per se, but if anything, a system using a monohydric or polyhydric alcohol having 4 or less carbon atoms as an alcohol is preferable, and the combination thereof has 10 to 32 carbon atoms. The ester of a fatty acid and an aliphatic monohydric alcohol is a system containing a fatty acid ester that is liquid at room temperature, or an ester of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms and monoglycerin or polyglycerin, which is hydrophilic. A system containing a fatty acid ester having a lipophilic balance of 9.0 or more is more preferable.

Further, if an example of the optimum range is shown on the basis of a specific combination, in the base which is a combination of isopropyl myristate, ethyl alcohol and water, isopropyl myristate is about 10% by volume based on the total amount. 1-30
%, Ethyl alcohol about 25-80%, water 5-60
%, And with a combination of isopropyl myristate, isopropyl alcohol and water,
Isopropyl myristate is about 1-50%, isopropyl alcohol is about 25-75%, and water is about 5-60%. Further, in the base which is a combination of isopropyl myristate, tert-butyl alcohol and water, isopropyl myristate is about 1-30%, tert-butyl alcohol is about 10-70% and water is about 5-80%. In the base which is a combination of isopropyl acid butyl alcohol and water, isopropyl myristate is about 1-40% and butyl alcohol is about 10-75.
%, Water is about 5-80%.

The above-mentioned base of the present invention itself has suitable moisturizing properties as a base for transdermal administration, skin spreadability, drug solubility, and properties necessary for a transdermal preparation, and an emulsion. It can be directly used as a base for preparations such as type lotions, patches, emulsion solutions, and sprays. In addition, transdermal preparations other than the above, for example, when used in ointments, creams, liniments, plasters, plasters, tapes, packs, suspensions, etc., in the base of the present invention Further, the required third component can be added. Examples of the third component include a cream-forming component in a cream, and the forming component is lanolin, propylene glycol, stearyl alcohol, petrolatum, silicone oil, liquid paraffin, glyceryl in the presence or absence of a surfactant. O / W called so-called cream in which ingredients such as monostearate are emulsified and dispersed in the water phase
Type, W / O type in which water is added to components such as petrolatum, higher aliphatic alcohols, liquid paraffin, etc. in the presence of a nonionic surfactant having few hydrophilic groups to emulsify and disperse There is.

When used as a suspending agent, it is used as a suspending agent in which starch, glycerin, high-viscosity carboxymethyl cellulose, carboxyvinyl polymer, etc. are added to water to form a gel, or a suspension-type lotion. In case of using, rubbers such as sodium alginate, gum arabic, pectin, tragacanth, methyl cellulose,
It suffices to blend an additive in which cellulose such as hydroxyethyl cellulose, clay such as bentonite and bee gum HV and water are mixed. When used as a liniment agent, the base of the present invention, for example, may be blended with vegetable oils such as olive oil, sesame oil, hemto oil, cottonseed oil, and turpentine oil, and when used as a poultice, Water-soluble polymers such as polyacrylic acid or its salts, polyvinyl alcohol, polyvinylpyrrolidone, etc., or those obtained by crosslinking water-soluble polymers with polyvalent metal salts such as alum, or physical properties such as irradiation of water-soluble polymers. What is crosslinked by a mechanical treatment may be added.

In addition to preservatives such as paraoxybenzoic acid, methylparaben, ethylparaben, propylparaben, chlorobutanol and benzyl alcohol, flavoring agents can be added to the base of the present invention. In addition to pH adjusters, various emulsifiers, dispersants, and
A wetting agent, a stabilizer, an antiseptic agent and the like can also be contained, and the pH adjusting agent is not particularly limited as long as it can be used in the field of formulation technology, and for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, Examples thereof include inorganic acids such as phosphoric acid, organic acids such as acetic acid, succinic acid, fumaric acid, malic acid, oxalic acid, lactic acid, glutaric acid, salicylic acid, tartaric acid, and salts thereof.

The base of the present invention can be manufactured by a conventional method, for example, by easily mixing a fatty acid ester, an alcohol, water and a necessary third component. Alternatively, a fatty acid ester may be added to an alcohol to be dissolved, and then water may be added to dissolve, emulsify or disperse the base to prepare a base, and then a necessary third component is added to knead, emulsify or suspend the mixture. For kneading, emulsifying, etc., a mixing device usually used in this technical field, such as a screw mixer, a homomixer, a kneader or a roll mill, can be used.

Further, as a transdermal preparation excellent in transdermal absorbability, which is another embodiment of the present invention, there may be mentioned the above-mentioned base of the present invention containing a pharmaceutical compound. As the pharmaceutical compound in the transdermal preparation of the present invention, any pharmaceutical compound can be adopted and is not particularly limited, but usually a drug that can be transdermally administered and is expected to have a systemic action or a local action is generally used. Target. A non-limiting list of such pharmaceutical compounds is, for example, specifically, clenazem [chemical name: (+)-(2S, 3S) -3-acetoxy-8-chloro-5- (2-dimethyl). Aminoethyl)-
2,3-dihydro-2- (4-methoxyphenyl)-
1,5-benzothiazepin-4- (5H) -one], diltiazem, Ca antagonists such as nifedipine, ACE inhibitors such as imidapril, enalapril, captopril, bisoprolol fumarate, denopamine, propranolol hydrochloride, isoproterenol hydrochloride, etc. Adrenaline β
Adrenergic α2 such as receptor blocker, clonidine
Anti-hypertensive agents such as receptor agonists, coronary vasodilators such as nitroglycerin, isosorbite nitrate, molsidomine, cardiac glycosides such as digoxin, cardiovascular drugs such as nicergoline and cerebral circulatory metabolism improving agents, diazepam , Imipramine and other neuroactive drugs.

Further, autonomic nerve agents such as dl-methylephedrine, antidepressants such as diphenhydramine, antipyretic and analgesic agents such as salicylic acid, and cranial nerve agents represented by cholinesterase inhibitors such as physostigmine, 8-hydroxy- Representative of bronchodilators such as 5-[(1R) -1-hydroxy-2- [N-((1R) -2- (p-methoxyphenyl) -1-methylethyl) amino] ethyl] carbostyril and epinephrine Respiratory drugs, digestive tract motility improvers such as trimebutine maleate, vitamins such as vitamin A, vitamin D, vitamin E and vitamin K, LH
-Represented by polypeptide hormones such as RH, TRH, calcitonin and ANP, endogenous opioid peptides such as endorphin and dynorphin, androgen agents such as testosterone, estrogen agents such as estradiol, and corticosteroids such as corticosteroids. Endocrine metabolism drug, 5-fluorouracil,
Antitumor agents typified by 6-mercaptopurine and the like, non-steroidal anti-inflammatory agents typified by aspirin, diclofenac, ibuprofen, indomethacin, ketoprofen and the like can also be mentioned. Further, these pharmaceutical compounds can be used in a free form or in the form of a pharmacologically acceptable salt thereof. Examples of the pharmacologically acceptable salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, salts with organic acids such as fumaric acid, maleic acid and acetic acid.

In the transdermal preparation of the present invention, as described above, it can be applied to almost all pharmaceutical compounds, but in particular, it can be suitably applied to lipophilic pharmaceutical compounds,
For example, when the distribution ratio in water-octanol is used as an index, the distribution ratio is about 10 ⁹ or less, preferably about 10 ^-7 -10 ⁷ , and most preferably about 10 ^-4 -10 ^6. preferable. When polyhydric alcohol is contained as a component of the base, the drug distribution rate is about 10
Of about ² -10 ⁶ are preferred.

In the transdermal preparation of the present invention, the compounding amount of the pharmaceutical compound is not particularly limited, and it depends on the pharmacological action of the pharmaceutical compound to be used, and the disease, age, symptom, body weight, and body weight of the patient to be administered. Although it may be determined in consideration of the administration site, for example, 0.01-20% (W /
It can be said that it is preferable to blend W or W / V) in the range of the properties of the preparation for transdermal administration. In addition, when a pharmaceutical compound such as vitamin D or various hormone preparations that can exert a medicinal effect in an extremely small amount is compounded, the compounding ratio can be further reduced.

A preferred group is shown more concretely by taking as an example the preparation for transdermal administration of the present invention, for example, a preparation containing lipophilic vitamins such as active vitamin D ₃ such as alfacalcidol and calcitriol as a pharmaceutical compound. As the agent, among the above-mentioned bases of the present invention, as a fatty acid ester, a) a fatty acid ester composed of a fatty acid having 1 to 32 carbon atoms and an aliphatic monohydric alcohol having 1 to 30 carbon atoms, and b) having 10 to 22 carbon atoms. Examples include fatty acid esters selected from esters of saturated or unsaturated fatty acids and glycerin, and alcohols as a base consisting of monohydric or polyhydric alcohols having 5 or less carbon atoms and water.

Of these, a more preferable base is
Examples include a base consisting of isopropyl myristate, ethanol and water, a base consisting of isopropyl caprate, ethanol and water, and the like.

Among the above-mentioned active vitamin D ₃ preparations, more preferable preparations are as follows: the fatty acid ester, alcohols and water are blended at a ratio of 1-50% of fatty acid ester and alcohols based on the total volume of these. Is 10-90
%, Water is 5-80%, and a preparation is prepared by adding active vitamin D ₃ which is a pharmaceutical compound to a base.

As described above, the active vitamin D ₃ preparation for transdermal administration of the present invention has excellent transdermal absorbability of a pharmaceutical compound and has a short half-life in vivo, compared with oral administration of active vitamin D ₃ . It is characterized by being able to maintain a stable plasma concentration for a long time with a small amount of administration, and active vitamin D
The side effects such as hypercalcemia that often occur with oral administration of ₃ can be reduced. Furthermore, it also has the feature that it can be made into an active vitamin D ₃ preparation that is stable for a long period of time by incorporating it into the above-mentioned base.

The transdermal preparation of the present invention has various dosage forms such as emulsion lotion, patch, emulsion solution, spray, ointment, cream, liniment, tape, pack and suspension. It can be adopted, and as described for the dosage form of the base, a desired preparation can be easily obtained by adding various optional components. For example, an emulsion type lotion is produced by mixing and stirring the pharmaceutical compound and the base of the present invention, and if necessary, adding an additive such as a colorant and a fragrance, mixing them, and filtering the mixture. Can be done.

The patch is a mixture of a pharmaceutical compound and a base,
It can be produced by impregnating a support, the liniment agent can be carried out by dissolving and mixing a pharmaceutical compound in a base, and the poultice is a pharmaceutical compound,
It can be produced by kneading a base and desired additives and spreading the mixture on a support. Hereinafter, the present invention will be described in more detail with reference to Experimental Examples and Examples.
This is not a limitation.

[0040]

[Action]

Experimental Example 1 Skin collected from the abdomen of Wistar male rats (body weight 250-300 g) that had been hair-removed with an electric hair clipper the day before was subjected to Franz diffusion cell (FDC-40).
0, manufactured by Crown Glass Co., USA). 37 ° C. constant temperature water was circulated in the jacket portion of this cell, and the receptor portion was filled with physiological saline.

Then, a transdermal administration base having the composition shown in Table 1 was added to 8-hydroxy-5-[(1R) -1-hydroxy-2- [N-((1R) -2- (p-methoxy) Phenyl) -1-methylethyl) amino] ethyl] carbostyryl hydrochloride was blended to give a 1% (W / V) solution, and 0.8 ml thereof was administered to the donor part. The concentration of the drug compound in the receptor portion was measured with HPLC over time, and the cumulative amount of permeation 8 hours after administration was determined. Result is,
It is as shown in Table 1.

[0042]

[Table 1]

Experimental Example 2 1% (W / V) of clentiazem maleate as a pharmaceutical compound was added to a transdermal administration base having the composition shown in Table 2.
It was dissolved or suspended so that Using 1 ml thereof, the same experiment as in Experimental Example 1 was carried out, and the cumulative amount of permeation of the pharmaceutical compound 8 hours after the administration was determined. The results are shown in Table 2.

[0044]

[Table 2]

Experimental Example 3 17β-estradiol as a pharmaceutical compound was added to a base for transdermal administration having the composition shown in Table 3 at a concentration of 0.1% (W / V) to be dissolved or suspended. Using 1 ml thereof, the same experiment as in Experimental Example 1 was carried out, and the cumulative amount of permeation of the pharmaceutical compound 8 hours after the administration was determined. The results are shown in Table 3.

[0046]

[Table 3]

Experimental Example 4 17β-estradiol as a pharmaceutical compound was added to a transdermal administration base having the composition shown in Table 4 to a concentration of 0.1% (W / V) and dissolved, and 20% was added to a receptor solution. (V
/ V) A permeation experiment was performed in the same manner as in Experimental Example 1 except that a physiological saline solution containing polyethylene glycol 400 was used, and the cumulative permeation amount after 8 hours was obtained. The results are shown in Table 4.

[0048]

[Table 4]

Experimental Example 5 To the transdermal administration base having the composition shown in Table 5, antipyrine was added as a pharmaceutical compound to a concentration of 1% (W / V) and dissolved, and 1 ml thereof was used to prepare Experimental Example 1. Similarly, the permeation experiment was performed. The cumulative amount of permeation (Y-axis) was plotted against time (X-axis), and the length was compared with the X-intercept where the slope of the linear portion was the drug permeation rate as the lag time. The results are shown in Table 5.

[0050]

[Table 5]

Experimental Example 6 <Purpose> Activated vitamin D ₃ was added to vitamin D deficient rats.
Is administered in a base consisting of isopropyl myristate-ethanol-water, the transdermal preparation of the present invention is administered,
The effects on blood calcium concentration and bone density were investigated.

<Preparation Method of Preparation> Active vitamin D ₃ was dissolved in a base consisting of isopropyl myristate-ethanol-water (composition ratio = 1: 4: 0.6) to a concentration of 0.01 μg / ml, This patch (2.5 cm 2) impregnated with 1 ml was used as a transdermal preparation of the present invention. 1 ml of the above-mentioned base as a control transdermal preparation
A patch agent impregnated with was prepared.

<Experimental Method> 3.5-week-old male Wistar rats were fed a vitamin D-deficient diet having a calcium content of 0.44% (experimental diet Diet 11, Nippon Clare Co., Ltd.).
After 2 weeks, the diet was further removed from Diet 11 for 1 week with a vitamin D deficient feed containing almost no calcium. 2 rats after breeding
The animals were divided into groups and returned to Diet 11 for rearing, and the drug-administered group was patched with active vitamin D ₃ and the control group was patched with only the base agent to remove hair. The rat was attached to the abdomen or back. The patch was applied twice a week in both groups for 7 consecutive weeks. Blood was collected from the jugular vein every week after administration, and the calcium concentration in plasma was measured by an atomic absorption method.

The femur was removed 7 weeks after the administration,
After drying under reduced pressure at 100 ° C. for 8 hours, the bone density of the rat femur was determined.

The bone density (BMD) was measured by a single photon absorption method using a bone mineral content measuring device (DCS-600, manufactured by Aloka Co.) and the bone mineral density (BMC) and the X-ray projected area (AR) of the bone.
EA) was measured and calculated as BMC / AREA.

<Results> The results are shown in Table 6 below. As a result, activated vitamin D ₃ was transdermally absorbed and promoted calcium absorption in the intestinal tract. As a result, the plasma calcium concentration was recovered to a normal value. did. On the other hand, in the control group to which only the base was applied, the plasma calcium concentration was further decreased, and normal solid feed (CRF) was administered for 3 to 7 weeks after the administration.
-1, the value was about half that of the normal group bred by Japan Charles River Co., Ltd.

On the other hand, the bone densities are shown in Table 7, and the bone densities of the vitamin D deficient rat group to which the transdermal preparation of the present invention was administered were significantly higher than those of the control group.

Further, as shown in FIG. 1, the bone density at each site when the femur was divided into five equal parts in the direction perpendicular to the long axis was also found in the vitamin D deficient rat group to which the transdermal preparation of the present invention was administered. It was higher than that in the control group at all sites.

[0059]

[Table 6]

[0060]

[Table 7]

Experimental Example 7 <Purpose> The bioavailability of normal rats administered with the transdermal preparation of the present invention in which active vitamin D ₃ was contained in a base consisting of isopropyl myristate-ethanol-water was examined. It was

<Preparation Method of Preparation> Active vitamin D ₃ is a base consisting of isopropyl myristate-ethanol-water (composition ratio = 1: 4: 0.6 or 1: 9.5: 9.
Dissolve in 5) to 0.1 μg / ml and add 1 ml
A patch (5 square centimeters) impregnated with was used as a transdermal preparation of the present invention. As a control transdermal preparation, active vitamin D ₃ was dissolved in ethanol to a concentration of 1 μg / ml, and a patch containing 1 ml of this was prepared.

<Experimental Method> Each patch was applied to the abdomen of the rat from which hair had been removed the day before. After application, 6 hours, 24 hours, 4
Blood was collected from the rat jugular vein at 8 hours. The plasma concentration of active vitamin D ₃ after transdermal administration was measured by the HPLC-RRA method, and the bioavailability thereof was compared.

<Results> The results are shown in Table 8 below. In the group to which the transdermal preparation of the present invention was administered, the results were 2 after administration.
A plasma concentration of 400-500 pg / ml persisted for 4-48 hours, but a 10-fold dose (1 μm) for the control formulation.
Even in g), almost the same as before administration, no increase in plasma concentration was observed.

[0065]

[Table 8]

[0066]

【Example】

Example 1 Isopropyl myristate 17.9% (V / V), ethyl alcohol 71.4% (V / V) and water 10.7%.
In a base material having a composition of (V / V), 0.1% (W / V
V) To a preparation containing 17β-estradiol at a concentration, 200 mg of hydroxypropylcellulose-SL (manufactured by Nippon Soda Co., Ltd.) was added and dissolved per 1 g of the preparation. Then, this was spread on a polyethylene sheet to form a circle having a radius of 1 cm to obtain a gel ointment.

About this transdermal preparation, 20% (V / V) polyethylene glycol 40 was used as a receptor solution.
The skin permeability of the medicinal compound was examined in the same manner as in Experimental Example 1 except that physiological saline containing 0 was used.
The cumulative amount of transmission after the lapse of time was 41.7 (μg / cm ² ). On the other hand, in an ethyl alcohol solution containing 17β-estradiol so as to have a concentration of 0.1% (W / V), hydroxypropyl cellulose-S was similarly added.
The cumulative amount of permeation of the transdermal preparation prepared by adding L after 24 hours was 3.0 (μg / cm ² ).

Example 2 8 g of petrolatum was added to a surfactant (trade name: Rheodor SP-
010; 0.1 g of Kao Corporation) was added, and 70-80 °
Heat to C and dissolve. After cooling this solution to 50-60 ° C, isopropyl myristate 17.9% (V
/ V), ethyl alcohol 71.4% (V / V) and water 10.7% (V / V) in the base, having a composition of 0.1
2 g of a mixture containing 17β-estradiol so as to have a concentration of (W / V) is gradually added with stirring. Then, this solution was cooled with stirring to obtain an ointment.

When this ointment was tested in the same manner as in Example 1 and the skin permeability of the pharmaceutical compound after 24 hours was examined, it was 12.4 (μg / cm ² ). On the other hand, a formulation of an ointment by adding an ethyl alcohol solution in which 17β-estradiol was dissolved to a concentration of 0.1% (W / V) to petroleum jelly containing Rheidol SP-010 as described above was 24 When the skin permeability of the pharmaceutical compound was examined after a lapse of time, 6.8 (μg /
cm ² ).

Example 3 Isopropyl myristate 17.9% (V / V), ethyl alcohol 71.4% (V / V) and water 10.7%
In a base having a composition of (V / V), 0.05% (W /
V) Vitamin D ₃ (calcitriol, manufactured by Wako Pure Chemical Industries, Ltd.) was used as a transdermal preparation of 1 ml, and 10% (V / V) polyethylene glycol 400 and 5% (V) were used as a receptor solution. / V) except that physiological saline containing ethanol was used, the same procedure as in Experimental Example 1 was carried out, and the cumulative amount of permeation 8 hours after administration was measured.
It was 2.1 (μg / cm ² ). On the other hand, a transdermal preparation containing 0.05% (W / V) of active vitamin D ₃ in ethyl alcohol, propylene glycol 9
7% (V / V) and Azone 3% (V
/ V) of the formulation containing 0.05% (W / V) of active vitamin D _{3 in the base} , the cumulative permeation amount after 8 hours is 0.1 (μg / cm ^2). )Met.

Example 4 0.05 g of imidapril, isopropyl myristate 17.9% (V / V), ethyl alcohol 71.4%
Dissolve in 30 ml of base having a composition of (V / V) and 10.7% (V / V) of water. Then this solution 0.3
A circular non-woven fabric having a diameter of 2.5 cm (ED-4150,
3 cm in diameter after impregnating with Nihon Bairin Co., Ltd.
4c diameter with aluminum foil stacked on top and adhesive applied
A patch was made by covering with m. polyvinyl chloride film.

This patch was applied to the abdomen of male Wistar rats (body weight: 250-300 g) dehaired the day before (dose: 2 mg / kg) and fixed with an elastic bandage,
Blood was collected from the jugular vein over time, and metabolites in plasma (chemical name:
(4S) -1-Methyl-3-[(2S) -2- [N-
((1S) -1-carboxy-3-phenylpropyl)
Amino-propionyl] -2-oxoimidazolidine-
The concentration of 4-carboxylic acid) was measured by radioimmunoassay. The results are as shown in Table 9.

[0073]

[Table 9]

The concentration of active metabolites in the blood when imidapril was dissolved in water to produce a patch as described above was below the detection limit.

Example 5 1 mg of active vitamin D ₃ (calcitriol) was added,
Isopropyl myristate 17.9% (V / V), ethyl alcohol 71.4% (V / V) and water 10.7%
Dissolve in 100 ml of base having a composition of (V / V).
Then, 1 ml of this solution was used as a patch in the same manner as in Example 4, and was transdermally administered to Wistar male rats, and blood was collected from the abdominal aorta, and blood active vitamin D ₃ after 24 hours and 48 hours were collected. The concentration was measured by HPLC. In addition, as a control formulation, 1 mg of active vitamin D ₃
After dissolving in 100 ml of ethyl alcohol, a patch preparation was prepared in the same manner as above, and the blood concentration of active vitamin D _{3 of} this preparation was measured by HPLC. The results are as shown in Table 10.

[0076]

[Table 10]

Example 6 A skin sensitization test tape (Fin Chamber, manufactured by Taisho Pharmaceutical Co., Ltd.) impregnated with a transdermal administration base having the composition shown in Table 11 below was applied to the upper bowl skin of a healthy subject. did. The skin was peeled off 7 hours after application, and the skin 24 hours after application was observed and evaluated. The judgment was made based on the following judgment criteria. The results are as shown in Table 11.

[0078]

[Table 11]

Example 7 Stearyl alcohol 6 g, polyethylene glycol 6
1 g of 000, 1,2,6-hexanetriol (1 g) was dissolved by heating at 80-85 ° C, and 17β-estradiol was added to a final concentration of 0.1% (W / W) and mixed. did. To this, separately heated to 80 ° C 1,
An ointment was prepared by adding a base consisting of 8.4 g of 3-butanediol, 1.8 g of water, 1.8 g of isosetyl isostearate, and 0.1 g of Rheidol SP-010, stirring and mixing until it solidified while cooling. Got

Example 8 Isocetyl isostearate 1.
An ointment was obtained by using 1.8 g of isopropyl caproate instead of 8 g.

Example 9 1 g of antipyrine was dissolved in 20 g of ethanol and 30 g of water. To this solution, 10 g of polyvinyl alcohol (completely saponified type, degree of polymerization: about 2000) is added, and the mixture is stirred with heating and dissolved. Next, 20 g of glycerin and 10 g of hexaglyceryl monolaurate are added and stirred. Finally, the whole amount is made up to 100 g with water and sufficiently stirred. Then, this was frozen and thawed to obtain a polyvinyl alcohol gel.

Example 10 0.5 g of carboxyvinyl polymer (Hibiswako 104, manufactured by Wako Pure Chemical Industries, Ltd.), 7.5 g of isopropyl alcohol, and 10 g of water were placed in a beaker and sufficiently stirred. 17β-estradiol was added to this so that the final concentration would be 0.1% (W / W), and then 2.5 g of isopropyl alcohol and 0.5 g of butyl stearate.
Is slowly added. While stirring the mixture,
Further, 0.25 g of diisopropanolamine was gradually added, and the mixture was stirred to obtain a highly viscous gel agent.

The gel permeation of 1 g was carried out in the same manner as in Example 1 and the skin permeation of the pharmaceutical compound after 8 hours was examined. As a result, it was 15.5 (μg / cm ² ). On the other hand, the final concentration should be 0.1% (W / W) 1
When isopropyl alcohol in which 7β-estradiol was dissolved was added to isopropyl alcohol containing carboxyvinyl polymer (Hibiswako 104) in the same manner as described above to form a gel, skin permeation of the pharmaceutical compound was examined after 8 hours. , 0.89 (μg /
cm ² ).

[0084]

INDUSTRIAL APPLICABILITY The present invention is a base in which three components of fatty acid ester, alcohols and water are combined, or a transdermal preparation in which a pharmaceutical compound is added to the base. Even a pharmaceutical compound that is relatively difficult to administer to the skin can pass through the stratum corneum of the skin with a high transmittance, and various pharmaceutical compounds can be efficiently and transdermally administered without using an absorption enhancer. It has an extremely excellent effect of being able to. It also has an excellent effect that the lag time until the medicinal compound is transdermally absorbed is short. In addition, these base ingredients have extremely low irritation to the skin, and therefore have the effect of being extremely safe even when formulated.

[Brief description of drawings]

FIG. 1 is a graph showing the bone densities of various sites of vitamin D-deficient rat femurs.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 47/10 N 7433-4C 47/14 E 7433-4C N 7433-4C

Claims (9)

[Claims] 1. A base for transdermal administration comprising a fatty acid ester, alcohols and water. 2. The base according to claim 1, wherein the fatty acid ester is a higher fatty acid ester and the alcohol is a monohydric or polyhydric alcohol. 3. Fatty acid ester, alcohol and water are about 0.1-50% of fatty acid ester and about 10-90% of alcohol, based on the total capacity of these three components.
The base according to claim 2, wherein water is blended in the range of about 1-80%. 4. The fatty acid ester (A) has 1 to 32 carbon atoms.
Is an ester of a fatty acid of 1 to 30 carbon atoms and an aliphatic monohydric alcohol having 1 to 30 carbon atoms, or (B) is an ester of a saturated or unsaturated fatty acid of 10 to 22 carbon atoms and mono- or polyvalent glycerin, and the alcohols are carbon atoms. The base according to claim 3, which is an alcohol having a number of 2 to 12. 5. A fatty acid ester is an ester of a fatty acid having 6 to 18 carbon atoms and an aliphatic monohydric alcohol having 3 to 20 carbon atoms, or an ester of saturated or unsaturated fatty acid having 12 to 18 carbon atoms and mono- or hexaglycerin. The base material according to claim 4, wherein the alcohol is a monohydric to trihydric alcohol having 2 to 4 carbon atoms. 6. The base according to claim 5, wherein the fatty acid ester is isopropyl myristate or isopropyl caprate, and the alcohol is ethanol. 7. A transdermal preparation containing the base according to claim 1 and a pharmaceutical compound. 8. The preparation according to claim 7, wherein the pharmaceutical compound is a lipophilic pharmaceutical compound. 9. The preparation according to claim 8, wherein the pharmaceutical compound is active vitamin D ₃ .